Novel LXR Agonists

Biological Mechanisms

Liver X receptors (LXRs) are nuclear receptors. There are two isoforms, LXRα and LXRβ, with LXRα mainly expressed in the liver, intestine, kidney and spleen, whereas LXRβ is ubiquitously expressed (Repa and Mangelsdorf 2000). Oxysterols and other cholesterol metabolites are natural ligands for LXRs, and several synthetic ligands were also developed (T0901317, GW3965). After their binding, LXRs modulate the expression of genes involved in cholesterol metabolism and transport and glucose metabolism (Schultz et al. 2000; Laffitte et al. 2003). Activation of LXR in macrophages induces ABCA1, ABCG1 and apoE expression which promotes cholesterol efflux and reverses cholesterol transport (Sabol et al. 2005; Venkateswaran et al. 2000; Laffitte et al. 2001). Besides their effects on lipid metabolism, LXRs display anti-inflammatory properties (Joseph et al. 2003) and improve glucose tolerance. In contrast to their beneficial effects, LXR activation induces fatty acid synthesis (de novo lipogenesis) related to a modulation of the hepatic expression of sterol regulatory element-binding protein (SREBP-1), stearoyl-CoA desaturase-1 (SCD-1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (Schultz et al. 2000). This upregulation of hepatic SREBP-1c expression may contribute to the elevation of plasma triglycerides.

Current State

T0901317 and GW3965, the most studied agonists, have been extensively described to exert beneficial effects in preclinical animal models of cardiovascular diseases, neurodegenerative diseases and inflammation (Terasaka et al. 2003; Joseph et al. 2002, 2003; Zelcer et al. 2007). However, LXR ligands have not yet been tested in clinical trials because of their adverse effects such as an increase of hepatic lipogenesis, hypertriglyceridaemia and hepatosteatosis (Calkin and Tontonoz 2012). These lipogenic effects have been assigned to LXRα which is highly expressed in the liver (Lehrke et al. 2005; Bradley et al. 2007). Therapeutic strategies are now focusing on the development of selective LXR modulators, LXRβ-specific agonists and/or ligands which act selectively in specific tissues in order to maintain positive effects on cholesterol metabolism and minimise the lipid side effects.

LXR-623 (WAY-252623) is a novel synthetic ligand with higher potency for LXRβ, which induces plaque regression in combination with statins in a rabbit model of atherosclerosis (Giannarelli et al. 2012). LXR-623 entered in a phase I trial (NCT00366522) to test tolerance and safety in humans (Katz et al. 2009). However, its development was interrupted because of adverse effects in the central nervous system with potential induction of psychiatric disorders.

Future Perspectives

A novel synthetic, steroidal LXR ligand, ATI-111, has been developed. This molecule is most potent on LXRα with modest effects on LXRβ. The higher efficiency on LXRα allows its utilisation at lower concentrations than T0901317, which probably reduces cytotoxicity and also adverse effects such as hypertriglyceridaemia. To determine whether ATI-111 does not provoke hypertriglyceridaemia, mice were treated with 5 of ATI-111 for 8 weeks. Interestingly, a decrease of plasma triglyceride levels and VLDL cholesterol was observed in ATI-111-treated mice (Peng et al. 2011). In addition, ATI-111 exhibits anti-inflammatory properties with a decrease of LPS-induced inflammatory gene expression. Furthermore, ATI-111 reduced atherosclerotic lesions in LDL-receptor-deficient mice (Peng et al. 2011). Altogether, accumulating proofs from in vitro and in vivo animal studies show beneficial effects of ATI-111 on atherosclerosis with anti-inflammatory effects, a reduction of hypertriglyceridaemia and a consequential decrease of atherosclerotic lesions. Further molecular investigations are necessary to assess the full potential of ATI-111 in clinical trials.

A phase I clinical trial with XL-652 (XL-014), a novel LXR ligand, is currently ongoing to evaluate its safety (

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